tbuckley/cabot-search huggingface dataset:
Expression of MMP2, MMP9 and PGP 9.5 in human aorta in patients with coronary artery disease
Authors: N Patel, R Chandrashekhar
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: None. Atherosclerosis has been recognised as inflammatory conditions which involves activation of MMPs of which increased MMP2 &amp; MMP9 expression has been correlated with the development of human aortic plaques.The Sympathetic Nervous System exerts complex control over inflammation in atherosclerosis both: on systemic scale and at the regional level.Protein gene product9.5 (PGP9.5) is a cytoplasmic neuron &amp; is a reliable marker for visualisation of the cardiovascular system innervation.There have been no studies in the existing literature on the expression of PGP 9.5 and MMP2, MMP9 on human aorta.Aim:To study the expression of MMP2, MMP9 and PGP9.5 in the human aorta &amp; gain insights into atherosclerosis &amp; neural modulation in the aorta.Materials &amp; Methods This is a single centre, prospective cohort, pilot study with a sample size of 87 patients,done over 2 years at AIMS,Kochi.During CABG, punch biopsy of the aorta taken &amp; processed.One paraffin embedded section used for routine H&amp;E staining &amp; others used for IHC.IHC detection kits use 3, 3’-DABChromogen as a substrate of HRP for visualisation of antigenic structures in the tissues.Positive &amp; negative control tissue were run for all 3 Antibodies.Interpretation done as Diffuse/Focal &amp; Intense/Moderate/ Weak classification based on intensity signals observed on IHC by an experienced Cardiac Pathologist.Results:7 Controls with well matched baseline characteristics: Controls-Aorta samples taken from patients who were undergoing Aortic Valve Surgery for Aortic Valve disease with normal coronaries documented on a coronary angiogram.65.9% of patients with Positive MMP2 &amp; 28.6 % of patients in the Control group was found to have significant difference when compared to positive &amp; negative outcomes amongst the 2 groups.89.3% of patients with positive MMP2 had significant co-relation with PGP9.5 levels expressed in the same specimen analysed.MMP9 also had a p value of 0.002 suggesting a significant co-relation between MMP9 &amp; PGP9.5.Statistically significant Co-relation seen between the Age, CRP &amp; the levels of MMP 9 expressed in the Aorta observed.MMP2 &amp; MMP9 expression have a definite &amp; significant co-expression with PGP9.5 expression in human aorta,suggesting a novel marker of neuromodulation in atherosclerotic process in human aorta. Expression of MMP2, MMP9 and PGP 9.5 in human aorta in patients with coronary artery disease
Innovative cancer nanomedicine based on immunology, gene editing, intracellular trafficking control
Authors: Yuma Yamada, Yusuke Sato, Takashi Nakamura, Hideyoshi Harashima
Journal: Journal of Controlled Release (2022)

The recent rapid progress in the area of drug delivery systems (DDS) has opened a new era in medicine with a strong linkage to understanding the molecular mechanisms associated with cancer survival. In this review, we summarize new cancer strategies that have recently been developed based on our DDS technology. Cancer immunotherapy will be improved based on the concept of the cancer immunity cycle, which focuses on dynamic interactions between various types of cancer and immune cells in our body. The new technology of genome editing will also be discussed with reference to how these new DDS technologies can be used to introduce therapeutic cargoes into our body. Lastly, a new organelle, mitochondria will be the focus of creating a new cancer treatment strategy by a MITO-Porter which can deliver macromolecules directly to mitochondria of cancer cells via a membrane fusion approach and the impact of controlled intracellular trafficking will be discussed.
A phase II trial of IDO-inhibitor, BMS-986205 (IDO), and PD-1 inhibitor, nivolumab (NIVO), in recurrent or persistent endometrial cancer (EC; CA017-056).
Authors: Chrisann Kyi, Maria M Rubinstein, Pooja Shah, Qin Zhou, Alexia Iasonos, Yue Liu, Lizbeth Ramirez, Viktoriya Paroder, Angela Green, Claire Frances Friedman, Rachel N. Grisham, Roisin Eilish O'Cearbhaill, Tiffany A. Troso-Sandoval, Seth M. Cohen, Stuart M. Lichtman, Jason A. Konner, Martee Leigh Hensley, Dmitriy Zamarin, Carol Aghajanian, Vicky Makker
Journal: Journal of Clinical Oncology (2022)

5589 Background: Indoleamine 2,3-dioxygenase 1 (IDO1) allows tumor escape through kynurenine production, which induces regulatory T cells and suppresses effector T-cell proliferation. NIVO, an anti-PD-1 inhibitor can upregulate IDO1, supporting the rationale for combining NIVO with IDO. We report results of NIVO as monotherapy and in combination with IDO inhibitor BMS-986205 in the treatment of pts with recurrent EC. Methods: In this single-institution, randomized phase 2 study, eligible pts must have received 1-4 prior lines of chemotherapy and have measurable disease by RECIST v 1.1. All EC histologies, including carcinosarcoma, were allowed. Pts with microsatellite insufficient (MSI-H) or mismatch repair (MMR)-deficient tumors were excluded. Pts were randomized to NIVO 480mg IV every 4 weeks (wks) with or without IDO 100mg orally daily. Primary endpoints were Overall Response Rate [ORR = Complete Response (CR) + Partial Response (PR)] by RECIST v 1.1. Secondary objectives were duration of response (DOR), median progression free survival (mPFS), PFS rate at 24 wks (PFS 24wks ) and safety. Overall survival (OS) was also evaluated. Results: Between 10/2019 and 11/2021, pts were randomized to receive either NIVO (n = 12) or NIVO + IDO (n = 12). Median age was 67 years (range 48-82) and median number of prior lines of therapy was 2 (range 1-3). Histologies included serous (n = 5, 21%), endometrioid (n = 10, 42%), clear cell (n = 1, 4.2%), carcinosarcoma (n = 6, 25%), undifferentiated (n = 1, 4.2%), and mucinous (n = 1, 4.2%). In the NIVO + IDO arm, 1 pt achieved partial response (8.3%, CI: 0.9-100%) with DOR of 17.6 months. In the NIVO arm, no responses were observed. Efficacy outcomes are summarized in the table. Treatment-related adverse events (TRAEs) grade ≥ 3 in the NIVO arm included acute kidney injury (n = 1, 8.3%), hypokalemia (n = 1, 8.3%), and thromboembolic event (n = 1, 8.3%). In the NIVO + IDO arm, TRAEs grade ≥ 3 included fatigue (n = 1, 8.3%), and elevated liver function (n = 1, 8.3%). No TRAEs led to study-drug interruption or dose reductions. Conclusions: NIVO monotherapy and in combination with IDO showed acceptable safety in pts with recurrent EC. NIVO in combination with IDO showed ORR of 8.3%. No responses were observed with NIVO monotherapy. The trial closed to accrual due to lack of observed clinical efficacy. Clinical trial information: NCT04106414. [Table: see text]
Genetic ancestry differences in tumor mutation in early and average-onset colorectal cancer.
Authors: Brooke Rhead, David Hein, Yannick Pouliot, Justin Guinney, Francisco De La Vega, Nina Niu Sanford
Journal: Journal of Clinical Oncology (2022)

3620 Background: The incidence and mortality of early onset colorectal cancer (EOCRC), defined as CRC diagnosed prior to age 50, are rising, in contrast to declining rates of average onset CRC (AOCRC). Epidemiologic trends for CRC appear to differ by race/ethnicity, which could be related in part to underlying differences in tumor mutation and gene expression. Previous research has used self-reported race/ethnicity categories, which has been shown to be missing or inaccurate, particularly in highly admixed groups such as Black and Hispanic patients. Hence, we examined tumor profiles of EOCRC and AOCRC using genetic ancestry. Methods: Genetic ancestry was inferred from de-identified data of 1,443 and 3,315 patients with EOCRC and AOCRC, respectively, who underwent tumor profiling with the Tempus xT NGS 648-gene panel and targeted RNAseq. Ancestry informative markers were used to estimate likelihoods for the five continental groups defined in the 1000 Genomes Project: Africa (AFR), Americas (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS). We assessed the association of genetic ancestry proportions (per 10% increase in each ancestry proportion) with presence of protein altering somatic mutations in key driver genes in CRC. We also assessed interactions between onset age (EOCRC vs. AOCRC) and genetic ancestry in somatic mutations. Results: Across all ages, African ancestry was associated with higher odds of mutations in APC and KRAS and lower odds of BRAF mutations (Table). East Asian ancestry was associated with higher odds of mutations in NTRK3 and TP53. For EOCRC, the association between KRAS and African ancestry remained significant (OR 1.07, p=0.04). Furthermore, there was an interaction (p=0.031) between onset age and race/ethnicity such that the association between African ancestry and APC mutation was significant in AOCRC (OR=1.09) but not EOCRC (OR=1.00). Conclusions: The use of genetic ancestry instead of categorical race/ethnicity provides a more quantitative and precise profile of shared genetic background that can underlie biological race differences in CRC cancer etiology and outcomes. [Table: see text]
Bendamustine rituximab (BR) versus ibrutinib (Ibr) as primary therapy for Waldenström macroglobulinemia (WM): An international collaborative study.
Authors: Jithma P. Abeykoon, Shaji Kumar, Jorge J. Castillo, Shirley D'Sa, Efstathios Kastritis, Eric Durot, Encarl Uppal, Pierre Morel, Jonas Paludo, Reema Tawfiq, Shayna Sarosiek, M Olabisi Ogunbiyi, Pascale Cornillet-Lefebvre, Robert A. Kyle, Alain Delmer, Morie A. Gertz, Meletios A. Dimopoulos, Steven P. Treon, Stephen M. Ansell, Prashant Kapoor
Journal: Journal of Clinical Oncology (2022)

7566 Background: Parenteral limited-duration BR chemoimmunotherapy and continuous orally administered Ibr, a Bruton tyrosine kinase inhibitor, dominate the treatment landscape of WM, a rare B cell lymphoma. No trials have assessed the comparative effectiveness of these 2 vastly different approaches. We conducted a multiinstitutional, international, collaborative study to compare BR and single-agent Ibr in patients (pts) with treatment naïve (TN) WM. Methods: Data from 347 pts with active TN WM, seen between 2011 and 2021 in the US and Europe, were analyzed. The pts on rituximab maintenance were excluded. The modified IWWM-6 criteria (based on IgM alone) were used for response assessment. All time-to-event analyses were performed from the frontline therapy initiation, using the Kaplan-Meier method. Results: The median age of the pts treated with BR (n=208) and Ibr (n=139) was 66 (range 40-86) years (y) and 69 (39-97) y, respectively, (p=0.005). With a median follow up of 4.2 y (95% CI 3.8-4.5), the 4-y progression free survival (PFS) was 73% in each group, p=0.6, and 4-y overall survival (OS) was 94% (95% CI 91-98) in the BR group versus ( v) 82% (95% CI 75-90) in the Ibr group, p=0.01. In a bivariate analysis adjusting for age and the treatment type, only age emerged as a predictor for OS (HR 7.2, p=0.0001). Therefore, a 1:1 age-matched analysis of 246 pts who received Ibr (n=123) or BR (n=123) was performed. Pts with a known MYD88 WT status who had received Ibr and their age matched controls on BR were excluded. The international prognostic scoring system (IPSS) WM was comparable between the 2 groups (Table). A higher proportion of pts on BR attained very good partial or deeper response (≥VGPR) as the best response in comparison to the pts on Ibr (Table). The 4-y PFS for the BR and Ibr groups was similar [72% (95% CI 63-82) v 78% (95% CI 70-87), p=0.14] and 4-y OS was 95% (95% CI 91-99) with BR v 86% (95% CI 80-93) with Ibr (p=0.3). Premature discontinuation, during active treatment, due to adverse effects (AEs) or lack of response was noted in 13% and 33% of pts on BR and Ibr, respectively. A detailed assessment of the AEs will be presented at the meeting. Conclusions: Both BR and Ibr lead to comparable outcomes in pts with TN WM, although deeper responses are attained with BR. These findings require confirmation in prospective studies. For pts who harbor MYD 88 L265P mutation, selection between the 2 approaches should be dictated by their potential toxicities, pt comorbidities, pt/clinician preference (parenteral fixed-duration v continuous oral) and access to therapies. [Table: see text]
Protein-spatiotemporal partition releasing gradient porous scaffolds and anti-inflammatory and antioxidant regulation remodel tissue engineered anisotropic meniscus
Authors: Bingbing Xu, Jing Ye, Bao-Shi Fan, Xinjie Wang, Ji-Ying Zhang, Shitang Song, Yifan Song, Wen-Bo Jiang, Xing Wang, Jia-Kuo Yu
Journal: Bioactive Materials (2022)

Meniscus is a wedge-shaped fibrocartilaginous tissue, playing important roles in maintaining joint stability and function. Meniscus injuries are difficult to heal and frequently progress into structural breakdown, which then leads to osteoarthritis. Regeneration of heterogeneous tissue engineering meniscus (TEM) continues to be a scientific and translational challenge. The morphology, tissue architecture, mechanical strength, and functional applications of the cultivated TEMs have not been able to meet clinical needs, which may due to the negligent attention on the importance of microenvironment in vitro and in vivo. Herein, we combined the 3D (three-dimensional)-printed gradient porous scaffolds, spatiotemporal partition release of growth factors, and anti-inflammatory and anti-oxidant microenvironment regulation of Ac2-26 peptide to prepare a versatile meniscus composite scaffold with heterogeneous bionic structures, excellent biomechanical properties and anti-inflammatory and anti-oxidant effects. By observing the results of cell activity and differentiation, and biomechanics under anti-inflammatory and anti-oxidant microenvironments in vitro, we explored the effects of anti-inflammatory and anti-oxidant microenvironments on construction of regional and functional heterogeneous TEM via the growth process regulation, with a view to cultivating a high-quality of TEM from bench to bedside.
Prophylactic lymphaticovenous bypass performed during complete lymphadenectomy is oncologically safe.
Authors: Cagri Cakmakoglu, Brian Gastman, Thomas Xia, Gregorz Kwiecien
Journal: Journal of Clinical Oncology (2022)

9557 Background: Lymphaticovenous anastomosis (LVA) is a physiologic surgery indicated for secondary lymphedema of the extremities, particularly for disease refractory to conservative management. Immediate lymphatic reconstruction (ILR) is prophylactic LVA concurrently performed with CLND. After the transected lymphatics are mapped through a dye injection, they are anastomosed to a nearby venous outflow tract. Though prophylactic LVA is increasingly being performed, its risk on cancer recurrence and distant metastasis is currently unknown. The purpose of this study was to compare the distant-metastasis free survival (DMFS) and relapse-free survival (RFS) times in melanoma patients who underwent prophylactic LVA during CLND versus those who underwent conventional CLND for grossly metastatic disease. Our study is the first prospective evaluation of the impact of prophylactic LVA on DMFS in patients undergoing CLND. Methods: This was a prospective study of patients with cutaneous melanoma who underwent CLND with concurrent LVA (LVA group) or CLND alone (comparison group) between 2012 and 2021. Patients were excluded if they had non-melanoma skin cancers, stage IV cancers before CLND, microscopic lymphatic disease only or follow-up time of less than 12 months who did not die from melanoma-related causes. The comparison group consisted of all consecutive patients that underwent CLND alone and met inclusion criteria. To reduce surgical technique variability, all cases were performed by a single, high-volume surgeon at a tertiary care center. Results: A total of 46 melanoma patients underwent prophylactic LVA during this time period. Twenty-three of these patients met all inclusion criteria and were included in the LVA group. Twenty-two consecutive patients that underwent CLND alone were included in the comparison group. All patients underwent either axillary or inguinal CLND. Average number of lymph nodes removed during CLND were 18.20 ± 9.61 and 17.04 ± 9.97 for the LVA and comparison groups, respectively (p = 0.69). Size of largest metastatic tumor in lymph nodes was 45.91 ± 35.03 mm and 44.54 ± 23.32 mm, respectively (p = 0.99). Average time to first recurrence diagnoses was 6.75 ± 3.54 months vs 8.28 ± 5.66 months. For distant metastases only, the average time to first recurrence diagnoses was 6.16 ± 3.79 months and 9.39 ± 6.19 months, respectively (p = 0.25). There was no significant difference in recurrence type between the two groups (p = 0.66). There were no differences in DMFS and RFS times between the LVA and comparison groups. Conclusions: Prophylactic LVA performed for grossly metastatic melanoma does not negatively impact DMFS nor RFS. Considering the extremely aggressive nature of melanoma, our finding is potentially applicable to other cancers that are amenable to CLND and LVA.
Imaging and physician visits at cancer diagnosis: COVID-19 pandemic impact on cancer care.
Authors: Rui Fu, Rinku Sutradhar, Qing Li, Timothy Hanna, Kelvin K. Chan, Natalie Coburn, Julie Hallet, Antoine Eskander
Journal: Journal of Clinical Oncology (2022)

1522 Background: Understanding how cancer system responded to the first wave of the COVID-19 pandemic has crucial implications to de-escalation measures in future waves. Here we examined the pandemic impact on the provision of diagnostic imaging (MRI, CT, and ultrasound) and physician visits (virtual and in-person) at cancer diagnosis in Ontario, Canada. Methods: For each week of June 26, 2016–September 26, 2020, we identified cancer diagnoses whose time around diagnosis (91 days +/- the date of diagnosis) fell into this week and restricted those diagnoses to be one per person-day and to patients aged 18+ at the beginning of that week. For these cancer patients, we used physician claims database to identify diagnostic imaging and visits received around cancer diagnosis. In separate segmented negative binomial regression procedures, we assessed the trends in weekly volume of these services per thousand cancer patients in pre-pandemic (June 26, 2016 to March 14, 2020), the change in mean volume at the start of the pandemic, and the additional change in weekly volume in the pandemic (March 15, 2020 to September 26, 2020). Results: Among 403,561 cancer patients in the cohort, 41,476 (10.3%) were diagnosed in the pandemic. As COVID-19 arrived, mean diagnostic imaging volume decreased by 12.3% (95% CI: 6.4%-17.9%) where ultrasound decreased the most by 31.8% (95% CI: 23.9%-37.0%) and MRI did not change (p-value = 0.27). Afterwards, the volume of all scans increased further by 1.6% per week (95% CI: 1.3%-2.0%), where ultrasound increased the fastest by 2.4% for each week (95% CI: 1.8%-2.9%). Mean in-person visits dropped by 47.4% when COVID-19 started (95% CI: 41.6%-52.6%) while virtual visits rose by 5515% (95% CI: 4927%-6173%). In the pandemic era, in-person visits increased each week by 2.6% (95% CI: 2.0%-3.2%), but no change was observed for virtual visits (p-value = 0.10). Conclusions: Provision of diagnostic imaging and virtual visits at cancer diagnosis has been increasing since the start of COVID-19 and already exceeded pre-pandemic utilization levels. These findings imply the feasibility of combining virtual consultations with diagnostic imaging to manage new cancer patients and highlight the need to monitor the quality of these services.
The case for simul-omics: Identifying IO biomarkers of ganitumab-metformin pathological complete response (pCR).
Authors: John R. Pfeiffer, Yuhan Zhang, Anu K. Antony, The SimBioSys Team, John A. Cole
Journal: Journal of Clinical Oncology (2022)

e12551 Background: During the I-SPY2 clinical trial, ganitumab (G) immunotherapy (IO) was co-administered with metformin (GM) to counteract G-induced hyperglycemia. The GM + standard of care (SOC) combination showed promising results but did not meet the statistical threshold for phase III. Predicting individual patient response to IO is a key limitation for clinical use and a reason why IO phase II to III oncology trial transitions fail. Thus, we used SimBioSys TumorScope (TS), a 4D spatiotemporal multiscale biophysical model, to identify predictive IO biomarkers of pCR in response to GM+SOC. Methods: Patients that received GM+SOC therapy (n=41) and SOC (n=41) matched controls from the I-SPY2 trial were included in analyses. Using SOC clinical data and DCE MRIs, we generated biophysical simulations of each individual patient’s response to SOC therapy. Derived from the TS simulation object of each patient, our “simul-omics” data represent tumor morphology, breast tissue proportions, drug response and delivery, and microvasculature-related feature sets. We also had access to the pre-treatment tumor biopsy-derived transcriptome microarray data. Predictive modeling was performed in a modular 3-step fashion: 1. clinical-only data to predict pCR, 2. clinical data plus candidate simul-omics data to predict pCR, and 3. available feature space for features that interact with treatment to provide the strongest predictive model of pCR. Results: The SOC data model (HR status, grade, treatment, age, race) predicted pCR with an accuracy (acc) of 0.67, sensitivity (sens)=0.71, specificity (spec)=0.66, and Cohen’s kappa=0.27. Simul-omic features median tumoral Kt at sim week 1 (acc=0.73), and tumoral pre-contrast small area emphasis (acc=0.77) improved model performance over SOC. When included in the same model, they increased predictive acc of the model to 0.79 (sens=0.64, spec=0.82, kappa=0.41). Simulation-derived features improved predictive power beyond SOC data. Exploratory search of the feature-space identified simul-omic features that would generate the most predictive models with a significant treatment interaction effect. Two simul-omics features added predictive strength to the model, with near-nominal interaction effects: phi_quant_90_regimen_wk22 (late timepoint mv density) (acc=0.84, kappa=0.58), and slopemap_tumor_glcm_clustershade (acc=0.86, kappa=0.60). We tested transcript expression as interaction terms in the model. The best performing model with an interaction effect was SHISA4 (acc=0.88, sens=0.86, spec=0.88, kappa=0.67). Conclusions: Our results show value in: 1. predicting pCR, the additive value of TS simulation data over just clinical/SOC data, 2. identification of potentially mechanistic drug targets facilitating GM response, and 3. potential to stratify patient populations into responder vs. non-responder categories prior to treatment.
Allergen Immunotherapy Reverses Immune Response to SARS-CoV-2 Vaccine in Patients with Allergic Rhinitis: A Prospective Observational Trial
Authors: Yin Yao, Ao Huang, Yi-Ke Deng, Yan Liu, Hong-Yu Zhu, Nan Wang, Zhe-Zheng Wang, Rong-Fei Zhu, Di Yu, Zheng Liu
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
Management aspects of urinary tract infection in diabetic patients: A national survey among different specialties
Authors: S. Zouari, A. Saadi, Y. Htira, I. Ben Nacef, M. Chakroun, S. Zaghbib, H. Boussaffa, A. Bouzouita, A. Derouiche, R. Ben Slama, K. Khiari, H. Ayed, M. Chebil
Journal: European Urology (2022)